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Epigenetic mechanisms are processes at the level of the chromatin that control the expression of genes but their role in neuro-immuno-endocrine communication is poorly understood. This review focuses on epigenetic modifications induced by a range of stressors, both physical and psychological, and examines how these variations can affect the biological activity of cells. It is clear that epigenetic modifications are critical in explaining how environmental factors, which have no effect on the DNA sequence, can have such profound, long-lasting influences on both physiology and behavior. A signaling pathway involving activation of MEK-ERK1/2, MSK1, and Elk-1 signaling molecules has been identified in the hippocampus which results in the phospho-acetylation of histone H3 and modification of gene expression including up-regulation of immediate early genes such as c-Fos. This pathway can be induced by a range of challenging experiences including forced swimming, Morris water maze learning, fear conditioning and exposure to the radial maze. Glucocorticoid (GC) hormones, released as part of the stress response and acting via glucocorticoid receptors (GRs), enhance signaling through the ERK1/2/MSK1–Elk-1 pathway and thereby increase the impact on epigenetic and gene expression mechanisms. The role of synergetic interactions between these pathways in adaptive responses to stress and learning and memory paradigms is discussed, in addition we speculate on their potential role in immune function.  相似文献   

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Low dose of D-cycloserine (DCS), a partial agonist of glycine binding site on N-methyl-D-aspartate (NMDA) receptors, can facilitate extracellular signal-regulated kinase1/2 (ERK1/2) activity in the amygdala and modulate emotional behavior. However, the relationship between ERK1/2 activation, individual anxiety levels, and DCS is unknown. Therefore, based on open arm time in the elevated plus-maze, male Wistar rats were divided into subgroups with either low (LOA) or high open arm (HOA) time. Open arm time is usually accepted as a critical index of unconditioned anxiety-like/avoidance behavior. On the following day, DCS (30 mg/kg, i.p.) was administered 30 min before the second elevated plus-maze test. On day 8 and 9, the rats were subjected to a 2-day session of the forced swim test, receiving the DCS treatment again 30 min before the 2nd day. On the 16th day, 30 min after the administration of DCS, the rats were sacrificed in order to detect the phosphorylation of ERK1/2 (p-ERK1/2) in the amygdala by Western blots. The results showed that: (1) DCS decreased the open arm time in HOA but not LOA rats. (2) DCS suppressed the immobility in the day-2 trial of the forced swim test and increased the p-ERK1/2 level in the amygdala in LOA but not HOA rats. This is the first instance data has been found indicating different sensitivities of p-ERK1/2 and behavioral responses to the treatment of DCS between HOA and LOA rats. The results suggest that the activity of NMDA receptor-mediated ERK1/2 signaling is mediated by individual behavioral differences which are related to the antidepressant-like activity of DCS. This study provides first insight into the pathophysiological role of ERK signaling with regard to individual differences in emotional behavior.  相似文献   

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Recent studies demonstrate that activation of Ca2+-permeable N-methyl-D-aspartate (NMDA) receptors upregulates phosphorylation of mitogen-activated protein kinases (MAPKs) in heterologous cells and neurons. In cultured rat striatal neurons, the present work systematically evaluated the role of a number of protein kinases in forming a signaling cascade transducing NMDA receptor signals to MAPKs. It was found that a brief NMDA application consistently induced rapid and transient phosphorylation of the extracellular signal-regulated kinase 1/2 (ERK1/2), a best characterized subclass of MAPKs. This ERK1/2 phosphorylation was resistant to the inhibition of protein kinase C, p38 MAPK, cyclin-dependent kinase 5, receptor tyrosine kinase (epidermal growth factor receptors), or non-receptor tyrosine kinases (including Src) by their selective inhibitors. However, the increase in ERK1/2 phosphorylation was partially blocked by a protein kinase A (PKA) inhibitor. The inhibitors for Ca2+/calmodulin-dependent protein kinase (CaMK) or phosphatidylinositol 3-kinase (PI3-kinase) completely blocked the NMDA-stimulated ERK1/2 phosphorylation. In an attempt to characterize the sequential role of CaMK and PI3-kinase, we found that NMDA increased PI3-kinase phosphorylation on Tyr508, which kinetically corresponded to the ERK1/2 phosphorylation and was blocked by the CaMK inhibitor. These results indicate that the protein kinases are differentially involved in linking NMDA receptors to ERK1/2 in striatal neurons.  相似文献   

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Both clinical and preclinical studies demonstrate the antidepressant activity of the functional NMDA receptor antagonists. In this study, we assessed the effects of two glycine/NMDA receptor ligands, namely L-701,324 (antagonist) and d-cycloserine (a partial agonist) on the action of antidepressant drugs with different pharmacological profiles in the forced swim test in mice. Swim sessions were conducted by placing mice individually in glass cylinders filled with warmed water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated. The locomotor activity of mice was measured with photoresistor actimeters. L-701,324 and d-cycloserine given with reboxetine (administered in subeffective doses) did not change the behavior of animals in the forced swim test. A potentiating effect was seen when both tested glycine site ligands were given concomitantly with imipramine or fluoxetine in this test. The lesion of noradrenaline nerve terminals produced by DSP-4 neither altered the baseline activity nor influenced the antidepressant-like action of L-701,324 or d-cycloserine. The depletion of serotonin by p-CPA did not alter baseline activity in the forced swim test. However, it completely antagonized the antidepressant-like action produced by L-701,324 and d-cycloserine. Moreover, the antidepressant-like effects of imipramine, fluoxetine and reboxetine were abolished by d-serine, a full agonist of glycine/NMDA receptors. The present study demonstrates that glycine/NMDA receptor functional antagonists enhance the antidepressant-like action of serotonin, but not noradrenaline-based antidepressants and such their activity seems to depend on serotonin rather than noradrenaline pathway.  相似文献   

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Retention of immobility in the Porsolt forced swim test is believed to be dependent upon glucocorticoid secretion in male rats. Because lactating females exhibit increased basal glucocorticoid secretion and blunted stress responses, we tested the hypothesis that lactation-induced changes in adrenal glucocorticoid and in circulating estrogen and progesterone levels would improve retention and/or acquisition of immobility. Immobility was recorded during 3 intervals of 5 min on day 1 (acquisition) and one 5 min interval 24 h later (retention). Blood samples were collected before the swim test and at various times after the onset of stress for plasma ACTH and corticosterone (B) determinations. Male rats (young = 200 g, old = 325 g) were compared to virgin females (V) and to lactating females in early (day 8-10, EL) and late (day 17–19, LL) lactation. Adrenalectomy (ADX) and ovariectomy (OVX) were performed 5 and 10 days prior to testing, respectively. All animals acquired immobility at the end of the 15 min swim on day 1, but only the young male group exhibited a significant retention of immobility on day 2. Total immobility was higher in males than females (V) although basal and stress-induced ACTH and B secretion were comparable on both testing days. Lactational status did not affect immobility in either the acquisition or retention phases. However, stress-induced ACTH secretion was greatly diminished in intact and ADX lactating females (EL and LL) compared to virgins (LL < EL < virgin), demonstrating a clear dissociation between behavioral and neuroendocrine responses. Following ADX, immobility in the retention phase was either decreased in males or increased in lactating females. Finally, OVX decreased immobility in both lactating (EL) and virgin females without significantly altering the magnitude of the ACTH and B responses to stress. In summary, our results demonstrated both sex-related and lactation-related differences in the behavioral and endocrine responses to the forced swim test of Porsolt. Although retention of the immobile response is thought to involve glucocorticoids and/or opioids secreted during the first testing session, we did not find evidence for a direct relationship between basal or stress-induced total corticosterone secretion, the magnitude of ACTH response to stress and behavioral scores in the retention period. However, experimental variables such as body weight, sex and water depth could significantly modify the outcome of behavioral testing and question the validity of glucocorticoid-mediated retention processes. Since the effect of ADX was reversed in lactating females compared to male rats, we hypothesize that glucocorticoid sensitivity of cognitive processes controlling behavioral reactivity is different from that controlling hypothalamic-adrenocortical function. Our results also demonstrated a clear dissociation between behavioral and neuroendocrine responses to the swim test, in particular during lactation. In early and late lactation, blunted responsiveness to stress was not caused by enhanced glucocorticoid feedback but might result from modifications in the inhibitiory and/or stimulatory inputs to hypothalamic neurons controlling adrenocortical activity.  相似文献   

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Epidemiological studies demonstrate that pain frequently occurs comorbid with depression. Gentiopicroside (Gent) is a secoiridoid compound isolated from Gentiana lutea that exhibits analgesic properties and inhibits the expression of GluN2B-containing N-methyl-d-aspartate (NMDA) receptors in the anterior cingulate cortex of mice. However, the effects of Gent on the reserpine-induced pain/depression dyad and its underlying mechanisms are unclear. Reserpine administration (1 mg/kg subcutaneous daily for 3 days) caused a significant decrease in the nociceptive threshold as evidenced by the reduced paw withdrawal latency in response to a radiant heat source and mechanical allodynia. Behavioral detection indicated a significant increase in immobility time during a forced swim test, as well as decreased time in the central area and total travel distance in an open field test. Furthermore, reserpinized animals exhibited increased oxidative stress. Systemic Gent administration dose-dependently ameliorated the behavioral deficits associated with reserpine-induced pain/depression dyad. At the same time, the decrease in biogenic amine levels (norepinephrine, dopamine, and serotonin) was integrated with the increase in caspase-3 levels and GluN2B-containing NMDA receptors in the amygdala of the reserpine-injected mice. Gent significantly reversed the changes in the levels of biogenic amines, caspase-3, and GluN2B-containing NMDA receptors in amygdala. However, Gent did not affect the expression of GluN2A-containing NMDA receptors. The inhibitory effects of Gent on oxidative stress were occluded by simultaneous treatment of GluN2B receptors antagonist Ro25-6981. Our study provides strong evidence that Gent inhibits reserpine-induced pain/depression dyad by downregulating GluN2B receptors in the amygdala.  相似文献   

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Serotonin transmission dysfunction has been suggested to play an important role in depression and anxiety. This study reports the results of a series of experiments in which rats were subjected to extended maize-based tortilla diets during early postnatal stages. This diet contains only approximately 20% of the L-tryptophan in normal diets of laboratory rodents. Compared with controls, experimental rats displayed a significant increase of immobility counts in the forced swimming test and exhibited anxiety-like behavior in the elevated plus maze test after 1 month of diet treatment. Low levels of serotonin contents were found in prefrontal cortex, striatum, hippocampus, and brainstem using high-performance liquid chromatography. Immunocytochemical reactions against 5-Bromo-2'-deoxyuridine revealed a significant decrease in the proliferation rate for the subgranular zone of dentate gyrus. c-Fos expression after the forced swimming test was found reduced in prefrontal cortex, dentate gyrus, CA1, and hilus of hippocampus and amygdala. Moreover, dendrite arbor atrophy and decreased spine density were evident in Golgi-Cox-impregnated CA1 pyramidal neurons. Abnormal dendrite swelling in dentate gyrus granule cells was also observed. These findings indicate an involvement of hyposerotoninergia in emotional disturbance produced by L-tryptophan restriction during critical developmental stages and suggest that neuroplasticity changes might underlie these changes.  相似文献   

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BACKGROUND: The enhanced depression-like behavior in the forced swim test displayed by rats selectively bred for high anxiety-related behavior (HAB) as compared with their low anxiety counterparts (LAB) is abolished by chronic paroxetine treatment. The aim of the present study was to identify neuronal substrates underlying this treatment response in HABs. METHODS: The HAB rats received paroxetine (10 mg/kg/day) for 24 days via drinking water, and drug-induced modulation of neuronal activation patterns in response to forced swimming was mapped with the expression of the immediate early gene c-Fos as marker. RESULTS: Chronic paroxetine treatment reduced the immobility scores during forced swimming, confirming the previously observed antidepressant-like effect in these animals, and attenuated the forced swim-induced c-Fos response in a restricted set (11 of 70) of brain areas. These included limbic areas such as the prelimbic cortex, parts of the amygdala, the bed nucleus of the stria terminalis, dorsal hippocampus, dorsal lateral septum as well as hypothalamic and hindbrain areas (dorsolateral periaqueductal gray [PAG], locus coeruleus). Untreated LAB rats, which displayed low depression-like behavior comparable to that of treated HABs, also showed low swim stress-induced c-Fos response in most of these same areas, further supporting an association of attenuated neuronal excitability in the identified areas with attenuated depression-like behavior. CONCLUSIONS: These findings indicate that modulation of neuronal activation in a restricted set of defined, mainly limbic as well as selected hypothalamic and hindbrain areas by paroxetine treatment is associated with the reduction of enhanced depression-like behavior in a psychopathological animal model.  相似文献   

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